Nor-LAAM loaded PLGA microparticles for treating opioid use disorder.

The treatment landscape for opioid use disorder (OUD) faces challenges stemming from the limited efficacy of existing medications, poor adherence to prescribed regimens, and a heightened risk of fatal overdose post-treatment cessation. Therefore, there is a pressing need for innovative therapeutic strategies that enhance the effectiveness of interventions and the overall well-being of individuals with OUD. This study explored the therapeutic potential of nor-Levo-α-acetylmethadol (nor-LAAM) to treat OUD. We developed sustained release nor-LAAM-loaded poly (lactic-co-glycolic acid) (PLGA) microparticles (MP) using a hydrophobic ion pairing (HIP) approach. The nor-LAAM-MP prepared using HIP with pamoic acid had high drug loading and exhibited minimal initial burst release and sustained release. The nor-LAAM-MP was further optimized for desirable particle size, drug loading, and release kinetics. The lead nor-LAAM-MP (F4) had a relatively high drug loading (11 wt%) and an average diameter (19 µm) and maintained a sustained drug release for 4 weeks. A single subcutaneous injection of nor-LAAM-MP (F4) provided detectable nor-LAAM levels in rabbit plasma for at least 15 days. We further evaluated the therapeutic efficacy of nor-LAAM-MP (F4) in a well-established fentanyl-addiction rat model, and revealed a marked reduction in fentanyl choice and withdrawal symptoms in fentanyl-dependent rats. These findings provide insights into further developing long-acting nor-LAAM-MP for treating OUD. It has the potential to offer a new effective medication to the existing sparse armamentarium of products available to treat OUD.

Development and comprehensive validation of a predictive prognosis model for very early HCC recurrence within one year after curative resection: a multicenter cohort study.

BACKGROUND: The high incidence of early recurrence after liver resection (LR) for hepatocellular carcinoma (HCC) is the main obstacle in achieving good long-term survival outcomes. The aim of the present study is to develop a prognostic model in predicting the risk of very early (1-year) recurrence. MATERIAL AND METHODS: Consecutive patients who underwent LR for HCC with curative intent at multicenters in China were enrolled in this study. The VERM-pre (the Preoperative Very Early Recurrence Model of HCC) with good performance was derived and validated by internal and external cohorts retrospectively and by another two-center cohort prospectively. RESULTS: Seven thousand four hundred one patients were enrolled and divided randomly into three cohorts. Eight variables (tumor diameter, tumor number, macrovascular invasion, satellite nodule, alpha-fetoprotein, level of HBV-DNA, γ-GT, and prothrombin time) were identified as independent risk factors for recurrence-free survival on univariate and multivariate analyses. The VERM-pre model was developed which showed a high capacity of discrimination (C-index: 0.722; AUROC at 1-year: 0.722)) and was validated comprehensively by the internal, external, and prospective cohorts, retrospectively. Calibration plots showed satisfactory fitting of probability of early HCC recurrence in the cohorts. Three risk strata were derived to have significantly different recurrence-free survival rates (low-risk: 80.4-85.4%; intermediate-risk: 59.7-64.8%; high-risk: 32.6-42.6%). In the prospective validation cohort, the swimming plot illustrated consistent outcomes with the beginning predictive score. CONCLUSION: The VERM-pre model accurately predicted the 1-year recurrence rates of HCC after LR with curative intent. The model was retrospectively and prospectively validated and then developed as the online tool.

Nor-LAAM loaded PLGA Microparticles for Treating Opioid Use Disorder.

The treatment landscape for opioid use disorder (OUD) faces challenges stemming from the limited efficacy of existing medications, poor adherence to prescribed regimens, and a heightened risk of fatal overdose post-treatment cessation. Therefore, there is a pressing need for innovative therapeutic strategies that enhance the effectiveness of interventions and the overall well-being of individuals with OUD. This study explored the therapeutic potential of nor-Levo-α-acetylmethadol (nor-LAAM) to treat OUD. We developed sustained release nor-LAAM-loaded poly (lactic-co-glycolic acid) (PLGA) microparticles (MP) using a hydrophobic ion pairing (HIP) approach. The nor-LAAM-MP prepared using HIP with pamoic acid had high drug loading and exhibited minimal initial burst release and sustained release. The nor-LAAM-MP was further optimized for desirable particle size, drug loading, and release kinetics. The lead nor-LAAM-MP (F4) had a relatively high drug loading (11 wt.%) and an average diameter (19 µm) and maintained a sustained drug release for 4 weeks. A single subcutaneous injection of nor-LAAM-MP (F4) provided detectable nor-LAAM levels in rabbit plasma for at least 15 days. We further evaluated the therapeutic efficacy of nor-LAAM-MP (F4) in a well-established fentanyl-addiction rat model, and revealed a marked reduction in fentanyl choice and withdrawal symptoms in fentanyl-dependent rats. These findings provide insights into further developing long-acting nor-LAAM-MP for treating OUD. It has the potential to offer a new effective medication to the existing sparse armamentarium of products available to treat OUD.

Dexamethasone sodium phosphate loaded nanoparticles for prevention of nitrogen mustard induced corneal injury.

Nitrogen mustard (NM) is a potent vesicating chemical warfare agent that is primarily absorbed through skin, inhalation, or ocular surface. Ocular exposure of NM can cause acute to chronic keratopathy which can eventually lead to blindness. There is a current lack of effective countermeasures against ocular exposure of NM despite their imperative need. Herein, we aim to explore the sustained effect of Dexamethasone sodium phosphate (DSP)-loaded polymeric nanoparticles (PLGA-DSP-NP) following a single subconjunctival injection in the management and prevention of corneal injury progression upon exposure to NM. DSP is an FDA approved corticosteroid with proven anti-inflammatory properties. We formulated PLGA-DSP-NP with zinc chelation ion bridging method using PLGA polymer, with particles of approximately 250 nm and a drug loading of 6.5 wt%. Under in vitro sink conditions, PLGA-DSP-NP exhibited a sustained drug release for two weeks. Notably, in NM injured cornea, a single subconjunctival (SCT) injection of PLGA-DSP-NP outperformed DSP eyedrops (0.1%), DSP solution, placebo NP, and saline, significantly mitigating corneal neovascularization, ulceration, and opacity for the two weeks study period. Through PLGA-DSP-NP injection, sustained DSP release hindered inflammatory cytokine recruitment, angiogenic factors, and endothelial cell proliferation in the cornea. This strategy presents a promising localized corticosteroid delivery system to effectively combat NM-induced corneal injury, offering insights into managing vesicant exposure.

The role of morphine- and fentanyl-induced impairment of intestinal epithelial antibacterial activity in dysbiosis and its impact on the microbiota-gut-brain axis.

Recent evidence suggests that chronic exposure to opioid analgesics such as morphine disrupts the intestinal epithelial layer and causes intestinal dysbiosis. Depleting gut bacteria can preclude the development of tolerance to opioid-induced antinociception, suggesting an important role of the gut-brain axis in mediating opioid effects. The mechanism underlying opioid-induced dysbiosis, however, remains unclear. Host-produced antimicrobial peptides (AMPs) are critical for the integrity of the intestinal epithelial barrier as they prevent the pathogenesis of the enteric microbiota. Here, we report that chronic morphine or fentanyl exposure reduces the antimicrobial activity in the ileum, resulting in changes in the composition of bacteria. Fecal samples from morphine-treated mice had increased levels of Akkermansia muciniphila with a shift in the abundance ratio of Firmicutes and Bacteroidetes. Fecal microbial transplant (FMT) from morphine-naïve mice or oral supplementation with butyrate restored (a) the antimicrobial activity, (b) the expression of the antimicrobial peptide, Reg3γ, (c) prevented the increase in intestinal permeability and (d) prevented the development of antinociceptive tolerance in morphine-dependent mice. Improved epithelial barrier function with FMT or butyrate prevented the enrichment of the mucin-degrading A. muciniphila in morphine-dependent mice. These data implicate impairment of the antimicrobial activity of the intestinal epithelium as a mechanism by which opioids disrupt the microbiota-gut-brain axis.

The adverse impact of perioperative body composition abnormalities on outcomes after split liver transplantation: a multicenter retrospective cohort study.

BACKGROUND: Split liver transplantation (SLT) increases graft availability, but it's safe and effective utilization is insufficiently documented. This study aimed to investigate the association between perioperative body composition abnormalities and outcomes in adult SLT. MATERIALS AND METHODS: Two hundred forty recipients who underwent SLT in three centers were enrolled in this retrospective cohort study. Body composition abnormalities including sarcopenia, myosteatosis, visceral obesity, and sarcopenic obesity were evaluated at baseline and 1 month after surgery using computed tomography. Their impact on outcomes including early allograft dysfunction, early complications, ICU stay, graft regeneration rate, and survival was analyzed. RESULTS: Recipients with sarcopenia or myosteatosis had a higher risk of early allograft dysfunction, higher early complication rate, and longer length of ICU stay (all P <0.05), while there was no difference in graft regeneration rate. Recipient and graft survival were significantly worse for recipients with body composition abnormalities (all P <0.05). In multivariable Cox-regression analysis, sarcopenia [hazard ratio (HR)=1.765, P =0.015], myosteatosis (HR=2.066, P =0.002), and visceral obesity (HR=1.863, P =0.008) were independently associated with shorter overall survival. Piling up of the three factors increased the mortality risk stepwise ( P <0.001). Recipients experienced skeletal muscle loss and muscle fat infiltration 1 month after surgery. Postoperative worsening sarcopenia (HR=2.359, P =0.009) and myosteatosis (HR=1.878, P =0.026) were also identified as independent risk factors for mortality. CONCLUSION: Sarcopenia, myosteatosis, and their progression negatively affect outcomes including early allograft dysfunction, early complications, ICU stay and survival after SLT. Systemic evaluation and dynamic monitoring of body composition are valuable.

Rational Construction of 3D Self-Supported MOF-Derived Cobalt Phosphide-Based Hollow Nanowall Arrays for Efficient Overall Water Splitting At large Current Density.

Developing efficient nonprecious bifunctional electrocatalysts for hydrogen and oxygen evolution reactions (HER and OER) in the same electrolyte with a low overpotential and large current density presents an appealing yet challenging goal for large-scale water electrolysis. Herein, a unique 3D self-branched hierarchical nanostructure composed of ultra-small cobalt phosphide (CoP) nanoparticles embedded into N, P-codoped carbon nanotubes knitted hollow nanowall arrays (CoPʘNPCNTs HNWAs) on carbon textiles (CTs) through a carbonization-phosphatization process is presented. Benefiting from the uniform protrusion distributions of CoP nanoparticles, the optimum CoPʘNPCNTs HNWAs composites with high abundant porosity exhibit superior electrocatalytic activity and excellent stability for OER in alkaline conditions, as well as for HER in both acidic and alkaline electrolytes, even under large current densities. Furthermore, the assembled CoPʘNPCNTs/CTs||CoPʘNPCNTs/CTs electrolyzer demonstrates exceptional performance, requiring an ultralow cell voltage of 1.50 V to deliver the current density of 10 mA cm-2 for overall water splitting (OWS) with favorable stability, even achieving a large current density of 200 mA cm-2 at a low cell voltage of 1.78 V. Density functional theory (DFT) calculation further reveals that all the C atoms between N and P atoms in CoPʘNPCNTs/CTs act as the most efficient active sites, significantly enhancing the electrocatalytic properties. This strategy, utilizing 2D MOF arrays as a structural and compositional material to create multifunctional composites/hybrids, opens new avenues for the exploration of highly efficient and robust non-noble-metal catalysts for energy-conversion reactions.

LAPTM4B-mediated hepatocellular carcinoma stem cell proliferation and MDSC migration: implications for HCC progression and sensitivity to PD-L1 monoclonal antibody therapy.

In hepatocellular carcinoma (HCC), immunotherapy is vital for advanced-stage patients. However, diverse individual responses and tumor heterogeneity have resulted in heterogenous treatment outcomes. Our mechanistic investigations identified LAPTM4B as a crucial gene regulated by ETV1 (a transcription factor), especially in liver cancer stem cells (LCSCs). The influence of LAPTM4B on LCSCs is mediated via the Wnt1/c-Myc/ß-catenin pathway. CXCL8 secretion by LAPTM4B drove myeloid-derived suppressor cell (MDSC) migration, inducing unfavorable patient prognosis. LAPTM4B affected PD-L1 receptor expression in tumor microenvironment and enhanced tumor suppression induced by PD-L1 monoclonal antibodies in HCC patients. LAPTM4B up-regulation is correlated with adverse outcomes in HCC patients, sensitizing them to PD-L1 monoclonal antibody therapy.

Heterogeneity-induced NGF-NGFR communication inefficiency promotes mitotic spindle disorganization in exhausted T cells through PREX1 suppression to impair the anti-tumor immunotherapy with PD-1 mAb in hepatocellular carcinoma.

BACKGROUND: The mechanism of decreased T cells infiltrating tumor tissues in hepatocellular carcinoma is poorly understood. METHODS: Cells were separated from the single-cell RNA-sequence dataset of hepatocellular carcinoma patients (GSE149614) for cell-cell communication. Flow cytometry, EDU staining, H3-Ser28 staining, confocal immunofluorescence staining, western blotting and naked microsubcutaneous tumors were performed for the mechanism of NGF-NGFR promoting proliferation. RESULTS: The present study has revealed that during the process of T-cell infiltration from adjacent tissues to tumor tissues, an inefficiency in NGF-NGFR communication occurs in the tumor tissues. Importantly, NGF secreted by tumor cells interacts with NGFR present on the membranes of the infiltrated T cells, thereby promoting the proliferation through the activation of mitotic spindle signals. Mechanistically, the mediation of mitotic spindle signal activation promoting proliferation is executed by HDAC1-mediated inhibition of unclear trans-localization of PREX1. Furthermore, PD-1 mAb acts synergistically with the NGF-NGFR communication to suppress tumor progression in both mouse models and HCC patients. Additionally, NGF-NGFR communication was positively correlates with the PD-1/PDL-1 expression. However, expressions of NGF and NGFR are low in tumor tissues, which is responsible for the invasive clinicopathological features and the disappointing prognosis in HCC patients. CONCLUSION: Inefficiency in NGF-NGFR communication impairs PD-1 mAb immunotherapy and could thus be utilized as a novel therapeutic target in the treatment of HCC patients in clinical practice.

Development of uniform fenofibrate-loaded biodegradable microparticle by membrane emulsification.

Fenofibrate has shown therapeutic effects on diabetic retinopathy. However, fenofibrate can be rapidly cleared from the eye after a single intravitreal injection. Here, we aim to develop fenofibrate loaded PLGA microparticles (Feno-MP) with high drug loading and sustained in vitro release up to 6 months suitable for intravitreal injection. First, orthogonal array experimental design was applied for formulation optimization. The selected formulation parameters were used to formulate Feno-MP using homogenization method and direct membrane emulsification method. Both methods generated Feno-MP with high drug loading and sustained in vitro drug release more than 140 days. Unlike the polydisperse Feno-MP prepared using homogenization method, membrane emulsification method generated Feno-MP with uniform size distribution. By controlling the membrane pore size, 1.5 µm, 8 µm and 16 µm Feno-MP were formulated and we found that larger Feno-MP demonstrated higher drug loading, more sustained drug release in vitro with less burst drug release than the smaller Feno-MP. In conclusion, we developed Feno-MP with high drug loading and sustained release profile, and elucidated that changing the particle size could have notable impacts on drug loading and release kinetics. Formulating Feno-MP with uniform size distribution by membrane emulsification method would benefit the batch-to-batch repeatability.

OsTCP19 coordinates inhibition of lignin biosynthesis and promotion of cellulose biosynthesis to modify lodging resistance in rice.

Lignin and cellulose are two essential elements of plant secondary cell walls that shape the mechanical characteristics of the culm to prevent lodging. However, how the regulation of the lignin and cellulose composition is combined to achieve optimal mechanical characteristics is unclear. Here, we show that increasing OsTCP19 expression in rice coordinately repressed lignin biosynthesis and promoted cellulose biosynthesis, resulting in enhanced lodging resistance. In contrast, repression of OsTCP19 coordinately promoted lignin biosynthesis and inhibited cellulose biosynthesis, leading to greater susceptibility to lodging. We found that OsTCP19 binds to the promoters of both MYB108 and MYB103L to increase their expression, with the former being responsible for repressing lignin biosynthesis and the latter for promoting cellulose biosynthesis. Moreover, up-regulation of OsTCP19 in fibers improved grain yield and lodging resistance. Thus, our results identify the OsTCP19-OsMYB108/OsMYB103L module as a key regulator of lignin and cellulose production in rice, and open up the possibility for precisely manipulating lignin-cellulose composition to improve culm mechanical properties for lodging resistance.

The Role of Morphine-Induced Impairment of Intestinal Epithelial Antibacterial Activity in Dysbiosis and its Impact on the Microbiota-Gut-Brain Axis.

Recent evidence suggests that chronic exposure to opioid analgesics such as morphine disrupt the intestinal epithelial layer and cause intestinal dysbiosis. Inhibiting opioid-induced dysbiosis can preclude the development of tolerance to opioid-induced antinociception, suggesting an important role of the gut-brain axis in mediating opioid effects. However, the mechanism underlying opioid-induced dysbiosis remains unclear. Host-produced antimicrobial peptides (AMPs) are critical for the integrity of the intestinal epithelial barrier as they prevent the pathogenesis of the enteric microbiota. Here, we report that chronic morphine exposure reduces expression of the antimicrobial peptide, Regenerating islet-derived 3 gamma (Reg3γ), in the ileum resulting in reduced intestinal antimicrobial activity against Gram-positive bacteria, L. reuteri. Fecal samples from morphine-treated mice had reduced levels of the phylum, Firmicutes, concomitant with reduced levels of short-chain fatty acid, butyrate. Fecal microbial transplant (FMT) from morphine-naïve mice restored the antimicrobial activity, the expression of Reg3γ, and prevented the increase in intestinal permeability and the development of antinociceptive tolerance in morphine-dependent mice. Similarly, oral gavage with sodium butyrate dose-dependently reduced the development of antinociceptive tolerance, and prevented the downregulation of Reg3γ and the reduction in antimicrobial activity. The alpha diversity of the microbiome was also restored by oral butyrate in morphine-dependent mice. These data implicate impairment of the antimicrobial activity of the intestinal epithelium as a mechanism by which morphine disrupts the microbiota-gut-brain axis.

The Role of Genetic Testing in Avoiding Diagnostic Delays in Inherited Retinal Disease.

PURPOSE: To identify and highlight potential delays in diagnosis and improve the characterization of the providers referring individuals affected with suspected IRDs for specialty care, we performed an analysis of the patients with IRDs seen by an ophthalmic genetics specialty service. In addition, we analyzed the diagnostic yield of genetic testing in patients with IRD in our series and compared this information with other previous studies. METHODS: We analyzed 131 consecutive patients with suspected IRDs referred to an ophthalmic genetics specialty service at a tertiary hospital. Provider referral patterns, delays in diagnosis and the diagnostic yield of genetic testing were evaluated. RESULTS: Mean age in the cohort was 24 years. From the 51 patients that underwent genetic testing, the diagnostic yield was 69%. Of these, genetic testing revealed 51% of patients had an incorrect initial referral clinical diagnosis. The average delay to reach a correct diagnosis was 15 years. Ophthalmologists represented the largest referral base at 80%, followed by neurologists representing 5% of referrals. Pediatric and retinal specialists were the largest referral of ophthalmic subspecialties at 44% and 35%, respectively. CONCLUSION: A significant number of patients experienced a prolonged delay in reaching a correct diagnosis largely due to a delay in initiating the genetic evaluation and testing process. The initial suspected clinical diagnosis was incorrect in a significant number of cases, revealing that affected patients were potentially denied from appropriate recurrence risk counseling, relevant educational resources, specialty referrals in syndromic cases, and clinical trial eligibility in a timely manner.

FOXM1 augments sorafenib resistance and promotes progression of hepatocellular carcinoma by epigenetically activating KIF23 expression.

Sorafenib has been used to enhance the survival outcome of hepatocellular carcinoma (HCC) patients. But, occurrence resistance to sorafenib subtracts from its therapeutic benefits. Herein, we identified that FOXM1 was markedly upregulated in both tumor samples and sorafenib-resistant HCC tissues. We also demonstrated that patients with decreased FOXM1 expression had longer overall survival (OS) and progression-free survival (PFS) in the cohort of sorafenib-treated patients. For HCC cells resistant to sorafenib, the IC50 value of sorafenib and the expression of FOXM1 were increased. In addition, Downregulation of FOXM1 expression alleviated the occurrence of resistance to sorafenib and reduced the proliferative potential and viability of HCC cells. Mechanically, the suppression of the FOXM1 gene resulted in the downregulation of KIF23 levels. Moreover, downregulation of FOXM1 expression reduced the levels of RNA polymerase II (RNA pol II) and histone H3 lysine 27 acetylation (H3K27ac) on the KIF23 promoter, further epigenetically silencing the production of KIF23. More intriguingly, our results similarly revealed that FDI-6, a specific inhibitor of FOXM1, suppressed the proliferation of HCC cells resistant to sorafenib, as well as upregulation of FOXM1 or KIF23 abolished this effect. In addition, we found that FDI-6 combined with sorafenib significantly improved the therapeutic effect of sorafenib. Collectively, the present results revealed that FOXM augments sorafenib resistance and enhances HCC progression by upregulating KIF23 expression via an epigenetic mechanism, and targeting FOXM1 can be an effective treatment for HCC.

Six-month effective treatment of corneal graft rejection.

Topical corticosteroid eye drop is the mainstay for preventing and treating corneal graft rejection. While the frequent topical corticosteroid use is associated with risk of intraocular pressure (IOP) elevation and poor patient compliance that leads to graft failure and the requirement for a repeated, high-risk corneal transplantation. Here, we developed dexamethasone sodium phosphate (DSP)-loaded dicarboxyl-terminated poly(lactic acid) nanoparticle (PLA DSP-NP) formulations with relatively high drug loading (8 to 10 weight %) and 6 months of sustained intraocular DSP delivery in rats with a single dosing. PLA DSP-NP successfully reversed early signs of corneal rejection, leading to rat corneal graft survival for at least 6 months. Efficacious PLA DSP-NP doses did not affect IOP and showed no signs of ocular toxicity in rats for up to 6 months. Subconjunctival injection of DSP-NP is a promising approach for safely preventing and treating corneal graft rejection with the potential for improved patient adherence.

New Air-Jet Dry Powder Insufflator for High-Efficiency Aerosol Delivery to Rats.

Pulmonary deposition of lung-targeted therapeutic aerosols can achieve direct drug delivery to the site of action, thereby enhancing the efficacy and reducing systemic exposure. In this study, we investigated the in vitro and in vivo aerosol performance of the novel small animal air-jet dry powder insufflator (Rat AJ DPI) using spray-dried albuterol excipient-enhanced-growth (EEG) powder as a model formulation. The in vitro aerosolization performance of the optimized albuterol EEG powder was first assessed using the Rat AJ DPI. The performance of Rat AJ DPI to deliver albuterol EEG aerosol to rat lungs was then compared to that of the Penn-Century Insufflator. Albuterol EEG powders dispersed using the Rat AJ DPI demonstrated narrow unimodal aerosol size distribution profiles, which were independent of the loaded powder dose (1, 2, and 5 mg). In addition, the span value for Rat AJ DPI (5 mg powder mass) was 1.32, which was 4.2-fold lower than that for Penn-Century insufflator (5 mg powder mass). At a higher loaded mass of 5 mg, the Rat AJ DPI delivered significantly larger doses to rat lungs compared with the Penn-Century DPI. The Rat AJ DPI with hand actuation delivered approximately 85% of the total emitted dose (2 and 5 mg loadings), which was comparatively higher than that for Penn-Century DPI (approximately 75%). In addition, percentage deposition in each of the lung lobes for the Rat AJ DPI was observed to be independent of the administration dose (2 and 5 mg loadings) with coefficients of variation below 12%, except in the right middle lobe. Automatic actuation of a 5 mg powder mass using the Rat AJ DPI demonstrated a similar delivered dose compared to manual actuation of the same dose, with 82% of the total emitted dose reaching the lung lobes. High-efficiency delivery of the aerosol to the lobar lung region and low sensitivity of the interlobar delivery efficiency to the loaded dose highlight the suitability of the new air-jet DPI for administering therapeutic pharmaceutical aerosols to small test animals.

Cell Features Reconstruction from Gene Association Network of Single Cell.

Gene expression as an unstable form of cell characterization has been widely used for single-cell analyses. Although there are cell-specific networks (CSN) to explore stable gene associations within a single cell, the amount of information in CSN is huge and there is no method to measure the interaction level between genes. Therefore, this paper presents a two-level approach to reconstructing single-cell features, which transforms the original gene expression feature into the gene ontology feature and gene interaction feature. Specifically, we first squeeze all CSNs into a cell network feature matrix (CNFM) by fusing the global position and neighborhood influence of genes. Next, we propose a computational method of gene gravitation based on CNFM to quantify the extent of gene-gene interaction, and we can construct a gene gravitation network for single cells. Finally, we further design a novel index of gene gravitation entropy to quantitatively evaluate the level of single-cell differentiation. The experiments on eight different scRNA-seq datasets show the effectiveness and broad application prospects of our method.

pH-Responsive Mucus-Penetrating Nanoparticles for Enhanced Cellular Internalization by Local Administration in Vaginal Tissue.

Low mucus penetration ability and cellular uptake seriously limit the effectiveness of local vaginal drug administration because of the rapid foreign particulate and pathogen removal property of the mucus layer. Our previous work proved that nanoparticles with a highly dense polyethylene glycol (PEG) coating can penetrate mucus rapidly (mucus-penetrating nanoparticles, MPPs) and improve drug distribution and retention at mucosal surfaces. However, the "stealth-effect" of the PEG coating also restricts cellular uptake of MPPs. In this work, we designed pH-responsive mucus-penetrating nanoparticles (pMPPs) with hydrazone bonds as the linker to conjugate a dense PEG surface coating, which enabled the pMPPs to rapidly penetrate through the mucus layer. More importantly, the acidic environment of the vaginal mucus induces slow shedding of the PEG layer, leading to a positive charge exposure to facilitate cellular uptake. Overall, pMPPs demonstrate potential as an effective delivery platform for the prophylactic and therapeutic treatment of female reproductive diseases.

Airway mucus in pulmonary diseases: Muco-adhesive and muco-penetrating particles to overcome the airway mucus barriers.

Airway mucus is a complex viscoelastic gel that provides a defensive physical barrier and shields the airway epithelium by trapping inhaled foreign pathogens and facilitating their removal via mucociliary clearance (MCC). In patients with respiratory diseases, such as chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), non-CF bronchiectasis, and asthma, an increase in crosslinking and physical entanglement of mucin polymers as well as mucus dehydration often alters and typically reduces mucus mesh network pore size, which reduces neutrophil migration, decreases pathogen capture, sustains bacterial infection, and accelerates lung function decline. Conventional aerosol particles containing hydrophobic drugs are rapidly captured and removed by MCC. Therefore, it is critical to design aerosol delivery systems with the appropriate size and surface chemistry that can improve drug retention and absorption with the goal of increased efficacy. Biodegradable muco-adhesive particles (MAPs) and muco-penetrating particles (MPPs) have been engineered to achieve effective pulmonary delivery and extend drug residence time in the lungs. MAPs can be used to target mucus as they get trapped in airway mucus by steric obstruction and/or adhesion. MPPs avoid muco-adhesion and are designed to have a particle size smaller than the mucus network, enhancing lung retention of particles as well as transport to the respiratory epithelial layer and drug absorption. In this review, we aim to provide insight into the composition of airway mucus, rheological characteristics of airway mucus in healthy and diseased subjects, the most recent techniques to study the flow dynamics and particle diffusion in airway mucus (in particular, multiple particle tracking, MPT), and the advancements in engineering MPPs that have contributed to improved airway mucus penetration, lung distribution, and retention.

Sirolimus improves the prognosis of liver recipients with hepatocellular carcinoma: A single-center experience.

BACKGROUND: Tumor recurrence after liver transplantation (LT) for selective patients diagnosed with hepatocellular carcinoma (HCC) in the setting of cirrhosis is the greatest challenge effecting the prognosis of these patients. The aim of this study was to evaluate the efficacy of sirolimus on the prognosis for these recipients. METHODS: The data from 193 consecutive HCC patients who had undergone LT from January 2015 to December 2019 were retrospectively analyzed. These patients were divided into the sirolimus group [patients took sirolimus combined with calcineurin inhibitors (CNIs) (n = 125)] and non-sirolimus group [patients took CNI-based therapy without sirolimus (n = 68)]. Recurrence-free survival (RFS) and overall survival (OS) were compared between the two groups. The prognostic factors and independent risk factors for RFS and OS were further evaluated. RESULTS: Non-sirolimus was an independent risk factor for RFS (HR = 2.990; 95% CI: 1.050-8.470; P = 0.040) and OS (HR = 3.100; 95% CI: 1.190-8.000; P = 0.020). A higher proportion of patients beyond Hangzhou criteria was divided into the sirolimus group (69.6% vs. 80.9%, P = 0.030). Compared with the non-sirolimus group, the sirolimus group had significantly better RFS (P < 0.001) and OS (P < 0.001). Further subgroup analysis showed similar results. CONCLUSIONS: This study demonstrated that sirolimus significantly decreased HCC recurrence and prolonged RFS and OS in LT patients with different stage of HCC.